The molecular events governing the onset and progression of malignant transformation involve oncogenic activation and inactivation of tumor suppressor genes, which help cancer cells overriding the normal mechanisms controlling cellular survival and proliferation (1,2). These molecular events are triggered by genetic alterations (translocations, amplification, mutations) and also by epigenetic modifications (3). Epigenetic modifications include methylation of DNA cytosine residues and histone modifications and have been shown to be critical in the initiation and progression of many cancers (4). DNA methyltransferase inhibitors or HDAC inhibitors are now being used in the treatment of some hematologic malignancies including multiple myeloma (MM) and myelodysplastic syndromes (5-8). 18 different HDACs were identified and divided into four classes based on cellular localization and function (9). Class I includes HDACs 1, 2, 3 and 8, which are restrictively nuclear. Class II HDACs includes HDACs 4, 5, 7 and 9 (class IIa) shuttling back and forth between the nucleus and the cytoplasm and HDACs 6 and 10 (class IIb), with their distinctive two zinc-dependent catalytic sites, are expressed only in the cytoplasm. Class III contains the NAD+ dependent sirtuin family, which does not act primarily on histones and class IV includes HDAC11 (9,10). Based on their chemical structure, HDACi can be grouped in four classes: hydroxamates (panobinostat, trichostatin-A (TSA), vorinostat, belinostat (PXD101), NVP-LAQ824 and givinostat (ITF2357)), cyclic peptide (romidepsin (depsipeptide)), aliphatic acids (valproic acid and sodium phenylbutyrate) and benzamides (MS-275, MGCD0103) (10). HDACi are characterized as class I-specific HDACs inhibitors (MGCD0103, romidepsin and MS-275) or as pan-HDAC inhibitors, denoting activity against both classes I and II HDACs (TSA, panobinostat, vorinostat and belinostat) (10). Multiple myeloma is a plasma cell neoplasm characterized by the accumulation of malignant plasma cells (PCs), termed Multiple Myeloma Cells (MMCs) within the bone marrow (BM). Despite the recent introduction of new therapies such as Lenalidomide and Bortezomib, MM remains an almost incurable disease. MM arises through the accumulation of multiple genetic changes that include an aberrant or overexpression of a D-type cyclin gene, cyclin D1 (CCND1) in the case of t(11; 14) translocation or gain in 11q13, cyclin D3 (CCND3) in the case of the rare t(6; 14) translocation, or cyclin D2 (CCND2) on the background of a translocation involving c-maf (t(14; 16)) or MMSET/FGFR3 (t(4; 14)) (11,12). HDACi have already been evaluated in MM including Trichostatin A (TSA) (13), vorinostat (14,15), NVP-LAQ824 (16), depsipeptide (17), KD5170 (18), valproic acid (19, 20) and panobinostat (10). In MM, HDACi induce G1 cell cycle arrest by enhancing expression of p21, p53 and dephosphorylation of Rb (13, 15, 20), induce apoptosis by dowregulation of Bcl-2 family members (15,17) and overcome drug resistance mediated by the bone marrow environment (15). Clinical trials were designed to analyze the activity of HDACi as single agents in Phase I/II trials in relapsed/refractory MM patients. When used as single agent, HDACi had modest activity (21,22), but in combination with other anti-MM treatments, they can induce durable responses (23,24).
The identification of biomarkers predictive for sensitivity of MMCs to HDACi is an important objective for optimizing these clinical trials. In the present invention, the inventors used gene expression profiling of Multiple Myeloma Cells (MMCs) to build a novel “histone acetylation gene expression score” that makes it possible identification of patients whose MMCs will be targeted by HDAC inhibition.